Green, versatile, and scale-up synthesis of amides by aerobic oxidative amination over Ag₂O/P-C₃N₄ photocatalyst

Highlights

• An atom & step economical method for photocatalytic synthesis of amides was developed.

• It is conducted under mild conditions using air as the oxidant & can be scaled up.

• It is superior to the known methods for functionlized amides especially for drug manufacture.

• The Ag₂O/P-C₃N₄ photocatalyst is reusable and imines as by products can be prevented.

• Interesting mechanism based on the strong adsorption of the sodium hemiamine was proposed.

Abstract

Being extensively applied in various fields of chemistry and chemical industry, the development of a green and versatile method for the synthesis of amides is in line with the demand of sustainable chemistry. Herein, a direct, highly selective, and scale-up (5–20 mmol) method for photocatalytic synthesis of amides through aerobic oxidative amination of alcohols with amines was developed under visible light, room temperature, using air as the oxidant. Benefiting from the adsorption of sodium hemiaminal on catalyst lengthens the CH bond (1.148 Å), this novel process is feasible for a broad range of functionlized amides (69 examples), especially those for drug manufacture (e.g., moclobemide and pipobroman). Imines was almost prevented with excellent amide selectivity up to 99 % could be ascribed to the low energy barrier for hemiaminal dehydrogenation while that for dehydration is high (2.13 eV). This green and efficient protocol represents an ideal alternative to the currently known methods.

Introduction

Amides are not only common chemicals in industry, but also ubiquitous structural units in organic functional compounds, materials, biologically active molecules, and drugs (Liu, et al., 2019). Nearly half of the top 200 selling pharmaceuticals contain amide bonds. The construction of amide bond is currently-one of the most widely used chemical protocols, accounting for about a quarter of the total reaction types (Mcgrath et al., 2010, Boström et al., 2018). The traditional methods for amide formation are based on the coupling of amines with carboxylic acid or boric acid derivatives (Scheme 1i), as well as nitrile hydrolysis and ketoxime rearrangement (Alandini et al., 2020, Lundberg and Adolfsson, 2015, Sabatini et al., 2019). They generally require the use of substrates that are hard to handle, and suffer from limited scope of substrates, poor tolerance of functional groups, and poor atom economy, as well as generation of substantial amount of chemical wastes (Gunanathan et al., 2007, Pattabiraman and Bode, 2011). Moreover, the harsh reaction conditions and/or separation of homogenous catalyst from the reaction system improved the investment, which don’t meet the requirements of today's green chemical industry. Therefore, it is highly desired to develop a facile approach to meet criteria such as versatile, environmentally friendly, and atom and step economic for the synthesis of both common amide chemicals and complex functional molecules, especially for those with sensitive functional groups.

On consideration of substrate availability, stability, and atom economy, cross-coupling of alcohols and amines has been considered as a promising alternative for amide bond formation (Scheme 1ii). Since the first report by Milstein et al. using ruthenium pincer complex as catalyst (Gunanathan, et al., 2007), the dehydrogenative coupling method has aroused tremendous attention (Wang et al., 2011, Dam et al., 2010, Ghosh et al., 2009, Ghosh and Hong, 2010, Gusev, 2017, Prechtl et al., 2012, Saha et al., 2014). Recently, oxidative dehydrogenative coupling protocols have been developed, with the aim of having water rather than explosive H₂ as by-product (Ye, et al., 2014). However, the catalysis is homogeneous and requires noble metal complexes and harsh reaction conditions, and limit of catalyst recovery, substrate scope and poor tolerance of functional groups is still a problem. Most of the reactions are applicable to generate secondary amines and/or benzyl amines. However, when primary alkyl amines are involved, undesired imines rather than amides are the main products. It is because through the dehydration of the commonly known intermediate (i.e., hemiaminals), there is the formation of imines and reduced selectivity to amides (Wang et al., 2011, Ventura-Espinosa et al., 2016, Jiang et al., 2021). Moreover, owing to the relatively low pKa, poor nucleophilicity of the aromatic amines, they often performed not well in the amination process (Drageset, et al. 2018) and undesired imines obtained as main products (Tolla, et al., 2021). So far, there is only one example of direct amidation of alcohols with aromatic amines (Wang, et al., 2011). Most of the reactions are limited to benzyl alcohols, and alkyl alcohols are rarely reported as efficient substrates. In the oxidative amination process, the generation of amide or imine depends on the priority of the dehydrogenation or dehydration pathways.

Photocatalytic aerobic oxidation of organics for the generation of functionalized compounds has aroused much interest because it proceeds under mild conditions with high selectivity (Nosaka and Nosaka, 2017). In the present study (Scheme 1iii), we anchored Ag₂O nanoparticles on P-doped C₃N₄ nanorods (denoted herein as Ag₂O/P-C₃N₄) and used the composite as a reusable photocatalyst (Zhang et al., 2020, Gaspa et al., 2020, Shah et al., 2020). Because of the strong interaction between Ag₂O nanoparticles and intermediates, the dehydrogenation process for amide formation is favored in the presence of photogenerated active •O₂^–. As expected, the photocatalyst functions extremely well in the oxidative amination of alcohols with stoichiometric amines using air as oxidant under visible light irradiation at room temperature. To our knowledge, this is the first report on heterogeneous photocatalyzed amination of alcohols towards amides, in which the photocatalyst could be easily isolated and reused. Moreover, this green and versatile method can be facilely applied for scale-up synthesis of amides. Each kind of amines (alkyl, benzyl, aryl, as well as heteroaryl primary amines and secondary amines) and alcohols (benzyl alcohols, heteroaryl methanols, alkyl alcohols) are well suited for the photocatalytic approach, demonstrating a broad scope of substrates for this kind of transformations. Using the mild and scale-up (at least 5 mmol) protocol, all kinds of amides can be produced in isolated yields of up to 98 % with excellent selectivity and outstanding functional group tolerance. It is revealed for the first time that the strong adsorption (adsorption energy: –2.95 eV) of the sodium hemiamine intermediate on Ag₂O/P-C₃N₄ causes the benyl CH bond to elongate (1.148 Å), which leads to excellent selectivity for aerobic oxidative dehydrogenation rather than dehydration.